The leukocyte common antigen (CD45) is a family of cell surface glycoproteins abundantly expressed on the surface of leukocytes. CD45 is composed of 5 different isoforms that are differentially expressed on T cells having different functional repertoires. Alterations in T cell subsets defined by these CD45 isoforms have been found in human immune-mediated disease states including renal transplantation and Lupus nephritis. Furthermore , these molecules appear to be directly involved in regulating cellular responses by potent interaction with activation signal pathways, and direct involvement in cytotoxic and suppressor function. While there has been great progress in our understanding of the primary structure of CD45, the genetic basis of the different isoforms (alternative splicing), and the biochemical activity of CD45 as a protein tyrosine phosphatase, none of the natural ligands or substrates for CD45 are known. Thus, we do not understand: 1) how these molecules interact with activation pathways to effect cell function. 2) what is the physiologic role of each isoform. 3) what is the nature and physiologic significance of shifts in isoform expression exhibited by individual T cells after activation. The studies in this proposal are designed to approach these gaps in our understanding about these important regulatory structures, integrating preliminary work by the applicant with techniques and methods already in use within the Division of Tumor Immunology at the Dana-Farber Cancer Institute.